[CIS PIDD] patient with susceptibility to herpetic infections

[Laia Alsina Manrique de Lara]

Dear all,

I follow in the Clinic a 5 yo male patient who displays a very narrow infectious phenotype (viral infections, herpetic in particular).

Here is the summary of the clinical history:

Date of Birth: 29/07/2007
Visit Date: 06/09/2012

Family history:
-No family history of consanguinity. Parents are from the Philippines. Patient was born in Spain. No family history of recurrent infections.

Personal history:
-Born preterm at 32 weeks, weight 1000 g (-2.6 SD), height 37 cm (-3DS). IUGR. Oligohydramnios. As neonatal complications, wet lung treated with CPAP during the first 30 hours of life.
- November 2007 (4 months of age): respiratory infection by influenza B virus (RSV-) and acute otitis media, requiring admission 1 week with oxygen.
- December 2007 (5 months of age): readmission for bronchiolitis. Condensation in right upper lobe and retrocardium. RSV-, flu -. After 2 weeks of admission he presents clinical worsening and was transferred to our hospital PICU for ventilatory support. BAL culture negative. Requires mechanical ventilation for 6 days with maximum FiO2 50%, followed by NIV for 4 days.
- January 2008 (6 months of age): two exacerbations of respiratory symptoms, with same radiological findings, which are managed as outpatient.  Associates diarrhoea with negative culture and ponderal stagnation.
- March 2008 (7 months): persistence of respiratory symptoms. Admitted to hospital. A viral load for CMV is detected in blood (2,058,000 copies / ml). Congenital CMV infection is ruled out: negative PCR in Guthrie card and negative PCR in mother's urine. No CMV VL can me determied in respiratory samples. Completed 14 days of ganciclovir. VL to CMV is well controlled --> diagnosed of acquired CMV infection with pneumonitis.
- July 2009 (2 years): severe varicella (generalized skin lesions that end up scarring as a major burn injury) with severe pneumonitis requiring mechanical ventilation for 9 days, complicated with ARDS. Source for VVZ: big brother at home. During intubation, lesions consistent with Candida in larynx and esophagus are observed. During this episode, the CV is reactivated CMV in blood and BAL.
- For the last 2 years, he has been suffering from recurrent upper respiratory tract infections and bronchitis. No other severe infections except fro a pneumonia in May 2011.
- July 2012: starts growth hormone treatment (no catch up in height at 4 yo, and past history of intrauterine growth retardation.
-Surgery for hypospadias.
-Correct vaccinations, including MMR (last dose in July 2012), no vaccine reaction.

Physical examination:
Weight 15 kg (3rd percentile)
Height 93 cm (3rd percentile)
Physical exam: No dysmorphic. Chickenpox scar lesions in skin.

Supplementary examinations (21/08/2012):
CBC: Hemoglobin 11.1 g / dl, Hematocrit 38.8%, Platelets 411 thousand / mmcc (150-500), Leukocytes 13.5 Mil / mmcc (5.0 to 13.0), absolute lymphocytes 5400/mm3. Monocytes: 0,6 Mil/mmcc (0,1-0,7).

B lymphocytes 12%  (21 to 28). Absolute 648 /mmcc (390-1400).
T lymphocytes 71% (62-69)
T4 lymphocytes 25% (30 to 40). Absolute 1350/mmcc (1000-1800).
T8 lymphocytes 45% (25-32)
T4/T8 Index 0.68  (1.00 to 1.60)
Natural Killer 8% (8 to 15) NKT cells present (see attached subphenotype of NK cells).
 --> Expansion of CD8 + and inversion of CD4/CD8 ratio.
 --> PCR to CMV, VVZ, EBV, herpes simplex are negative.

Immunoglobulins
Immunoglobulin G 19640 mg / L (4540-12000)
Immunoglobulin A 1415 mg / L 244-1510
Immunoglobulin M 1868 mg / L 436-1890
Immunoglobulin E <1 KIU / L 0-59
IgG subclasses
Immunoglobulin G1 15763 mg / L 3200-9000
Immunoglobulin G2 1727 mg / L 520 to 2800
Immunoglobulin G3 2766 mg / L 140-1200
Immunoglobulin G4 19 mg / L 10-1060

 --> Expansion of IgG1 and IgG3.

Other studies
-Study NK cytotoxicity and degranulation:
--16/01/2012 Cytotoxicity reduced but not absent, with increased expression of perforin in CD8 + with respect to control (indicates hyper-activation of CTLs).
--19/03/2012: Normal, both cytotoxicity and degranulation.

-Test of lymphocyte proliferation to mitogens (PHA and PWD): normal
-T lymphocyte phenotyping: normal (alphabeta populations: 91%, gammadelta 7.5%, RO+: 24%; RA+: 65%).
-CD18 expression: normal
-MHC class 1 expression: normal

-Isohemagglutinins and protein and polysaccharide vaccine responses: normal

-Ab VVZ IgG positive
-Ab CMV IgG positive

High resolution lung CT (16/01/2012): no bronchiectasis. Mild diffuse air trapping. There are some small bilateral subpleural dense linear image, probably related to discrete changes of pulmonary dysplasia secondary to prematurity.



Diagnosis:

-increased susceptibility to viral infections, herpetic in particular.

-a combined immunodeficiency is ruled out.

-might be a functional NK cell deficiency?



My questions regarding this patient are:
1- Do you suspect a paticular PIDD? What other immunological tests would you perform?
2- What management do you suggest? (early treatment of infections, IVIG?).



Thank you very much for your help,


Dra. Laia Alsina
Sección de Alergia e Inmunología Clínica
Hospital Sant Joan de Déu
Passeig Sant Joan de Déu nº2
08950 Esplugues de Llobregat, Barcelona
+34932804000 ext 3330
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